Tetracycline-novobiocin compositions and method of use



United States Patent Office 3,220,925 Patented Nov. 30, 1965 3,220,925TETRACYCLINE-NOVOBIOCIN COMPOSITIONS AND METHOD OF USE Louis C.Schroeter, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo,Mich, a corporation of Delaware No Drawing. Fiied Nov. 15, 1962, Ser.No. 238,051 12 Claims. (Cl. 167-82) This invention relates to antibioticcompositions and, more particularly, to a combination of tetracyclineand novobiocin with which higher antibiotic blood levels can beobtained.

Tetracycline and novobiocin in combination have been widely used in thetreatment of a number of bacterial infections with outstanding success.The combination has been reported to be particularly useful in delayingthe onset of antibiotic resistance by initially susceptible pathogens.Despite the efiicacy of this combination, it has been recognized that insome instances lower blood levels of novobiocin are obtained when thetwo antibiotics in powder form are administered in the same dosage unitas compared with blood levels resulting from the administration ofnovobiocin alone. This problem has been studied by various groups, butno satisfactory explanation or solution to the problem has heretoforebeen available.

It has now been found that the administration of a solid oral dosageunit comprising tetracycline and novobiocin as the essential activeingredients can be prepared which gives optimum novobiocin andtetracycline blood levels. This is accomplished by providing thenovobiocin in the form of from about 5 to about 2000 pellets, preferablycoated with a pharmaceutically acceptable material which will delayrelease on the novobiocin from about to about 20 minutes after reachingthe stomach. During this period the tetracycline will dissolve and bediluted by gastric contents and the novobiocin pellets dispersed beyondthe site of tetracycline release and dissolution.

The term tetracycline as employed herein embraces all forms oftetracycline, including specifically the bases tetracycline,chlortetracycline, oxytetracycline and demethylchlortetracycline, and inparticular the pharmaceutically acceptable acid addition salts of thesebases, such as the hydrochloride, hydrobromide, phosphate, phosphatecomplexes (e.g., as described in US. Patent No. 2,791,609), and thelike.

The term novobiocin includes all forms of novobiocin absorbable from theintestinal tract and employed in therapy, specifically, novobiocin,amorphous (but not crystalline) novobiocin acid, and thepharmaceutically acceptable alkali metal and alkaline earth metal saltsof novobiocin such as sodium novobiocin and calcium novobiocin.

As employed herein the term pellets describes discrete particles, suchas granules, compressed powders, pilules, spheres and the like, havingan integrity suflicient to withstand formulation into a single dosageunit such as a hard gelatin capsule, soft gelatin capsule or tablet.These pellets, prepared in conventional manner, can range in size fromabout 0.3 mm. to about 6.0 mm. in diameter, or in their longestdimension if not round, depending on the number to be incorporated ineach dosage unit and the limitations on size of the dosage unit. Theshape of the pellets is unimportant except insofar as coatingconsiderations are concerned, but they should be essentially uniform insize (for example, between 16 and 20 mesh and free from powders finerthan about 50 mesh). Pellets comprising granules can be prepared, forexample, by conventional wet or dry (slugging) techniques.

Studies have indicated that a portion of the novobiocin, whenincorporated as a powder with tetracycline powder in a single capsule,is converted to crystalline novobiocin acid when the capsule is ingestedand reaches the acidic fluids of the stomach. Although novobiocinitself, even as an amorphous acid, is normally absorbed withoutdifficulty from the intestinal tract, crystalline novobiocin acid isrelatively insoluble and is not absorbed in significant amounts. Thesurfaces of novobiocin particles exposed to gastric juices, andespecially to high concentrations of tetracycline solution, areconverted to crystalline novobiocin acid. The purpose of the pellets ofnovobiocin is therefore to render the novobiocin in a form more readilytransportable through peristaltic movement to various parts of thestomach away from the vicinity of tetracycline release and dissolution.The optional provision of these pellets with a coating which will delayrelease of the novobiocin in the stomach for about 10 to 20 minutesafter reaching the stomach assures that the surfaces of these pelletswill not, in the course of dispersing, be exposed to locally highconcentrations of tetracycline solution and develop the insolublecrystalline novobiocin acid coating. A further advantage of the coatingis to thwart the tendency of these pellets to be enveloped by thecrystalline coating, which otherwise would interfere with the dispersiveprocess.

The provision of novobiocin in pellet form accomplishes also theobjective of achieving a steady, statistically predictable release ofnovobiocin to the intestinal tract in absorbable form whereby optimumand dependable blood levels of novobiocin can be obtained, In general,from about 50 to about 500 pellets of novobiocin provides a distributionin the stomach sufficient to give a favorable discharge rate into theintestinal tract through normal stomach emptying. A broader range offrom about 5 to about 2000 pellets, while embracing marginal regions,nevertheless alfords a distribution and rate of discharge into theabsorption regions which satisfies the requirements of this invention.

Styrene maleic acid copolym'er, utilized as described in US. Patent No.2,897,121, is admirably suited as a coating material in the presentinstance. In general, coating thickness should be sufficient to provideprotection to the pellets or granules against disintegration insimulated gastric fluid (0.05 N hydrochloric acid at 37 C.) for 10 to 20minutes. Other pharmaceutically acceptable coating materials can beemployed to delay release of the novobiocin in the stomach. Suchcoatings include, for example, fatty or waxy materials (mono-, di? ortriglycerides, beeswax and the like) and hydrophobic polymers (ethylcellulose and the like) in thicknesses calculated to give the desiredrelease delay. Suitable coatings include, in addition, those describedin Remingtons Practice of Pharmacy, 12th Edition, 1961, pages 483-485.

Advantageously, but not necessarily, the novobiocin pellet formulationcan include a surfactant of the anionic or non-ionic type in order tofacilitate the dissolution of novobiocin on breakdown of the pellets.Pharmaceutically acceptable anionic surfactants such as dioctyl sodiumsulfosuccinate, sodium 'lauryl sulfate and the like are prefered for usewith sodium novobiocin. The nonionic surfactants, such as polysorbate80, are likewise acceptable. Cationic surfactants are not suitablebecause of their tendency to interact with sodium novobiocin to forminsoluble novobiocin salts or crystalline novobiocin acid.

Combinations of tetracycline and novobiocin preferably contain fromabout 50 to about 500 mg. of tetracyline and from about 50 to about 500mg. of novobiocin for the treatment of bacterial infections in mammals.Such combinations, formulated in accord with this invention andadministered on the usual schedule for the combination, give bloodlevels of tetracyline and novobiocin in humans and animals approximatingEXAMPLE l.HARD GELATIN CAPSULES One kilogram of sodium novobiocin isprepared in pellet form by first mixing with 20 gm. of magnesiumstearate and gm. of a mixture of 85 dioctyl sodium sulfosuccinate andsodium benzoate.- The. resulting mixture is screened through a No. 40screen and blended for 30 minutes. Pellets are then formed by slugging.Approximate size of the resulting pellets is 0.03l-inch thick and0.045-inch diameter.

The pellets above are coated by air suspension with an alcoholicsolution of 1.5% styrene maleic acid copolymer and 0.3% n-dibutylphthalate to a thickness of 0.5 mm.

Hard gelatin No. 0 capsules are then filled with 125 mg. of sodiumnovobiocin as pellets (approximately 150 pellets) and 250 mg. oftetracycline hydrochloride powder.

EXAMPLE 2.SOFT GELATIN CAPSULES Granules are prepared from the followingmaterials:

Sodium novobiocin 125 Spray dried lactose 85% dioctyl sodiumsulfosuccinate and 15% sodium benzoate 2 Silicon dioxide 1 Magnesiumstearate 1 After slugging, the large tablets or slugs are broken down tothe correct size by forcing them through a 14-20 mesh screen using anoscillating granulator. Granules are classified according to size byscreening so that all granules pass through a No. 20 screen (0.84 mm.)but not through a No. screen (0.59 mm.). The granules are coated as inExample 1. Soft gelatin capsules are then filled with a mixture of 125mg. of sodium novobiocin as coated granules and 250 mg. of tetracyclinehydrochloride.

EXAMPLE 3.--HARD GELATIN CAPSULES Fifty million coated pilulescontaining sodium novobiocin are prepared from the followingingredients:

Pill starters 50,000,000

An unmeasured quantity of bolted sucrose (30-40 mesh per square inchscreen) is placed in a revolving pill tub and moistened with a spray ofdeionized or distilled water until uniformly moistened. Uniformity insize of the bolted sucrose is more important at this stage that is therelative size of the sucrose granules. A small amount of a homogeneousmixture of bolted talc, starch and sucrose (100 mesh per square inchscreen) in a ratio of 20:5:1 is dusted on the moistened sucrose. Thetalc-starch-sucrose mixture rolls onto the moistened sucrose. Thecontents of the pill tub are alternately water-sprayed and powder-dusteduntil spherical masses (pill starters), having a diameter between 0.020and 0.021 inch, are produced. The smaller spheres are separated from thelarger ones by screening during processing. They are returned to thepill tub and brought up to the proper size by the above describedmethod. Those spheres which are out of shape at this point arediscarded. Only round, smooth starters are used to form pilules.

4 Medicinal agent mixture Sodium novobiocin kg. 44.6 Starch, bolted kg.3.4 Sucrose, powdered kg. 1.7 Talc kg. 6.2 Dioctyl sodium sulfosuccinategm. 400

The sodium novobiocin and an equal amount of the starch are uniformlymixed and the mixture is micronized. 'The mixture is then blended withthe remaining starch and other ingredients and bolted through No. 11cloth.

Coating solution Kg. Hydrolysed styrene-maleic acid copolymer 5.4 Whitemineral oil, 180 viscosity 0.9 Denatured ethanol, anhydrous 28 Thecopolymer is dissolved in the alcohol and the mineral oil is added.- Itis preferred to use 0.5 kg. of n-dibutylphthalate as plasticizer in thecoating solution.

Directions: (a) The pill starters are sprayed in a revolving pill tubwith deionized water until uniformly moistened.

(b) The medicinal agent mixture is dusted on the moistened starters. Thespraying and dusting are repeated until the average diameter of thepilules is from 0.035-0.038 inch. The pilules are air dried and assayedfor sodium novobiocin content.

(c) The assayed pilules are coated with the coating solution by the airsuspension technique until the average diameter is increased by0.00050.0008 inch. The coated pilules are assayed for sodium novobiocincontent.

(d) The coated pilules are encapsulated into twopiece hard gelatincapsules each containing mg. of sodium novobiocin in the form ofdelayed-coated pilules and 250 mg. of powdered tetracyclinehydrochloride.

What is claimed is:

1. A solid oral dosage unit comprising, as essential active ingredients,powdered tetracycline and novobiocin, said novobiocin being separatedfrom said tetracycline by being in the form of from about 5 to about2000 pellets.

2. A solid oral dosage unit comprising: as essential active ingredients,powdered tetracycline and novobiocin, said novobiocin being in the formof from about 5 to about 2000 pellets coated with a pharmaceuticallyacceptable material which will delay release of the novobiocin fromabout 10 to about 20 minutes after reaching the stomach to permit thetetracycline to dissolve and be diluted by gastric contents andnovobiocin pellets to disperse beyond the site of tetracycline releaseand dissolution.

3. A solid oral dosage unit comprising: as essential active ingredients,powdered tetracycline and novobiocin, said novobiocin being in the formof from about 50 to about 500 pellets containing novobiocin admixed witha surfactant selected from the group consisting of anionic and non-ionicsurfactants and coated with a pharmaceutically acceptable material whichwill delay release of the novobiocin from about 10 to about 20 minutesafter reaching the stomach to permit the tetracycline to dissolve and bediluted by gastric contents and novobiocin pellets to disperse beyondthe site of tetracycline release and dissolution.

4. A capsule for therapeutic use comprising: as essential activeingredients, from about 50 to about 500 mg. of powdered tetracycline andfrom about 50 to about 500 mg. of novobiocin, said novobiocin being inthe form of from about 50 to about 500 pellets containing novobiocinadmixed with a surfactant selected from the group consisting of anionicand non-ionic surfactants and coated with styrene maleic acid copolymer.

5. A capsule for therapeutic use comprising: as essential activeingredients, about 250 mg. of powdered tetracycline and about 125 mg. ofnovobiocin, said novobiocin being present in the form of pelletscontaining novobiocin admixed with diocytyl sodium sulfosuccinate andcoated with styrene maleic acid copolymer.

6. A method for obtaining higher novobiocin blood levels from a singledosage unit containing tetracycline and novobiocin than results fromadministering powdered tetracycline and powdered novobiocin together ina single dosage unit, which method comprises: administering to mammals asingle dosage unit containing powdered tetracycline and novobiocin, saidnovobiocin being in the form of from about 5 to about 2000 pellets.

7. A method for obtaining higher novobiocin blood levels from a singledosage unit containing tetracycline and novobiocin than results fromadministering powdered tetracycline and powdered novobiocin together ina single dosage unit, which method comprises: administering to mammals asingle dosage unit containing powdered tetracycline and novobiocin, saidnovobiocin being in the form of from about 50 to about 500 pelletscoated with a pharmaceutically acceptable material which will delayrelease of the novobiocin from about to about minutes after reaching thestomach to permit the tetracycline to dissolve and be diluted by gastriccontents and novobiocin pellets to disperse beyond the site oftetracycline release and dissolution.

8. A method for obtaining higher novobiocin blood levels from a singledosage unit containing tetracycline and novobiocin than results fromadministering powdered tetracycline and powdered novobiocin together ina single dosage unit, which method comprises: administering to mammals asingle dosage unit containing powdered tetracycline and novobiocin, saidnovobiocin being in the form of from about 50 to about 500 pelletscontaining novobiocin admixed with a surfactant selected from the groupconsisting of anionic and non-ionic surfactants and coated with apharmaceutically acceptable material which will delay release of thenovobiocin from about 10 to about 20 minutes after reaching the stomachto permit the tetracycline to dissolve and be diluted by gastriccontents and novobiocin pellets to disperse beyond the site oftetracycline release and dissolution.

9. A method for obtaining higher novobiocin blood levels from a singledosage unit containing tetracycline and novobiocin that results fromadministering powdered tetracycline and powdered novobiocin together ina single dosage unit, which method comprises: administering to mammals asingle dosage unit containing from about to about 500 mg. of powderedtetracycline hydrochloride and from about 50 to about 500 mg. of sodiumnovobiocin, said sodium novobiocin being in the form of from about 50 toabout 500 pellets containing sodium novobiocin admixed with surfactantselected from the group consisting of anionic and non-ionic surfactantsand coated with styrene maleic acid copolymer.

10. A method for obtaining higher novobiocin blood levels from a singledosage unit containing tetracycline and novobiocin than results fromadministering powdered tetracycline and powdered novobiocin together ina single dosage unit, which method comprises: administering to humansand animals a single dosage unit containing about 250 mg. of powderedtetracycline hydrochloride and about mg. of sodium novobiocin, saidsodium novobiocin being present in the form of pellets containing sodiumnovobiocin admixed with dioctyl sodium sulfosuccinate and coated withstyrene maleic acid copolymer.

11. A solid oral dosage unit comprising: as essential activeingredients, about 250 mg. of powdered tetracycline and about 125 mg. ofnovobiocin, said novobiocin being in the form of from about 50 to about500 pellets.

12. A method for obtaining higher novobiocin blood levels from a singledosage unit containing tetracycline and novobiocin than results fromadministering powdered tetracycline and powdered novobiocin together ina single dosage unit, which method comprises: administering to mammals asingle dosage unit containing about 250 mg. of powdered tetracycline andabout 125 mg of novobiocin, said novobiocin being in the form of fromabout 50 to about 500 pellets.

References Cited by the Examiner UNITED STATES PATENTS 2,928,770 3/1960Bardani 167-82 2,954,323 12/1960 Endicott et al. 16782 2,994,639 8/1961Carper et al. 167-65 3,070,501 12/1962 Mullins et al. 16765 JULIAN S.LEVITT, Primary Examiner.

8. A METHOD FOR OBTAINING HIGHER NOVOBIOCIN BLOOD LEVELS FROM A SINGLEDOSAGE UNIT CONTAINING TETRACYCLINE AND NOVOBIOCIN THAN RESULTS FROMADMINISTERING POWDERED TETRACYCLINE AND POWDERED NOVOBIOCIN TOGETHER INA SINGLE DOSAGE UNIT, WHICH METHOD COMPRISES: ADMINISTERING TO MAMMALS ASINGLE DOSAGE UNIT CONTAINING POWDERED TETRACYCLINE AND NOVOBIOCIN, SAIDNOVOBIOCIN BEING IN THE FORM OF FROM ABOUT 50 TO ABOUT 500 PELLETSCONTAINING NOVOBIOCIN ADMIXED WITH A SURFACTANT SELECTED FROM THE GROUPCONSISTING OF ANIONIC AND NON-IONIC SURFACTANTS AND COATED WITH APHARMACEUTICALLY ACCEPTABLE MATERIAL WHICH WILL DELAY RELEASE OF THENOVOBIOCIN FROM ABOUT 10 TO ABOUT 20 MINUTES AFTER REACHING THE STOMACHTO PERMIT THE TETRACYCLINE TO DISSOLVE AND BE DILUTED BY GASTRICCONTENTS AND NOVOBIOCIN PELLETS TO DISPERSE BEYOND THE SITE OFTETRACYCLINE RELEASE AND DISSOLUTION.